Startseite Synthesis of novel thiourea-/urea-benzimidazole derivatives as anticancer agents
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Synthesis of novel thiourea-/urea-benzimidazole derivatives as anticancer agents

  • Lamia A. Siddig , Mohammad A. Khasawneh , Abdelouahid Samadi , Haythem Saadeh EMAIL logo , Nael Abutaha EMAIL logo und Mohammad Ahmed Wadaan
Veröffentlicht/Copyright: 26. Oktober 2021
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Open Chemistry
Aus der Zeitschrift Open Chemistry Band 19 Heft 1

Abstract

A new series of urea and thiourea derivatives containing benzimidazole group as potential anticancer agents have been designed and synthesized. The structures of the synthesized compounds were characterized and confirmed by spectroscopic techniques such as 1H NMR, 13C NMR, and mass spectrometry. In vitro anticancer assay against two breast cancer (BC) cell lines, MDA-MB-231ER(−)/PR(−) and MCF-7ER(+)/PR(+), revealed that the cytotoxicity of 1-(2-(1H-benzo[d]imidazol-2-ylamino)ethyl)-3-p-tolylthiourea (7b) and 4-(1H-benzo[d]imidazol-2-yl)-N-(3-chlorophenyl)piperazine-1-carboxamide (5d) were higher in MCF-7 with IC50 values of 25.8 and 48.3 µM, respectively, as compared with MDA-MB-231 cells. Furthermore, 7b and 5d were assessed for their apoptotic potential using 4′,6-diamidino-2-phenylindole, acridine orange/ethidium bromide staining, and Caspase-3/7. After incubation with MCF-7, the compounds 7b and 5d induced apoptosis through caspase-3/7 activation. In conclusion, the compounds 7b and 5d are potential candidates for inducing apoptosis in different genotypic BC cell lines.

Keywords: benzimidazole; urea; thiourea; piperazine; anticancer activity; apoptosis

1 Introduction

Benzimidazole is a very useful heterocycle for the development of molecules of pharmaceutical and biological interest. Compounds containing benzimidazole have been widely used in drug development and researchers around the world are actively seeking new uses and applications [1]. Benzimidazole derivatives have found applications in diverse therapeutical areas including antimicrobial [2,3,4], antifungal [5,6,7,8], antiviral [9,10], antitubercular [11,12,13], antidiabetic [14,15], anti-inflammatory [16,17], antihistaminic [18], antioxidant [19,20], and anticancer activities [21,22]. Moreover, benzimidazoles are one of the early classes of anticancer agents such as bendamustine Figure 1 [23]. In addition, many derivatives showed anticancer activity against human liver carcinoma (HEP-G2) cell lines [22], while others derivatives possess potent anticancer activity against other human cancer cell lines [16] such as MCF-7, THP-1, PC-3, and A-549. Thiourea and urea are classes of organic compounds which have a wide diversity and multiple applications. Their derivatives demonstrate a broad range of pharmacological activities such as antimicrobial, antidiabetic, analgesic, and anticancer activities [24,25,26]. Several anticancer agents containing urea and thiourea functional groups reached clinical phases [27] such as Tandutinib and Enzalutamide, respectively (Figure 1). Moreover, novel series of benzimidazole-thiourea [28] and benzimidazole-urea [29] derivatives were synthesized and they exhibited potent antiproliferative activity against a group of human tumor cells compared to standard drugs. Hybrids of urea and benzimidazole showed potent anticancer activity and some derivatives are already in the drug market such as Glasdegib [30] (Figure 1).

Figure 1 Potent anticancer agents.
Figure 1

Potent anticancer agents.

According to the World Health Organization (WHO), the number of people diagnosed with cancer increased from 10 million in 2000 to 19.3 million in 2020. Breast cancer (BC) is the world’s most diagnosed cancer as reported by International Agency for Research on Cancer (IARC) in 2020 (WHO, 2021) with metastasis and drug resistance being the main challenge for successful treatments [31]. Moreover, the drug resistance of cancer cells exerts more pressure to look for new effective chemotherapeutic agents. BC is subtyped or classified based on their genotypic differences and metastasis characteristics. The toxicity of the drug against different types of BC cells differs significantly due to variation in the metabolic outcome of their genotype [32,33].

Apoptosis is an important biological event that takes place in multicellular organisms to remove unwanted or damaged cells [34]. Apoptosis has been extensively used for therapeutic applications and biological studies and huge effort has been dedicated to the discovery of apoptosis-inducing molecules that may have antitumor potential [35].

Based on the biological activity profile of benzimidazole derivatives and thiourea and urea derivatives, the current study is aimed to synthesize novel thiourea- and urea-benzimidazole derivatives and evaluate their anticancer activity against two different cancer cell lines (MDA-MB-231ER(−)/PR(−) and MCF-7ER(+)/PR(+)) with different genotypic features.

2 Experimental methods

2.1 Materials and methods

Melting points were determined in open capillary tubes using the Sanyo Gallenkamp MPD 350-BM 3.5 Melting Point apparatus (UK), and are uncorrected. FT-IR spectra were recorded in a Thermo Nicolet Nexus 470 FT-IR spectrophotometer (USA). 1H NMR and 13C NMR spectra were recorded at room temperature in CDCl3 or DMSO-d 6 as a solvent using Varian-400 MHz (USA). Solvent peaks (CDCl3: 7.26 [D] and 77.2 [C] ppm and DMSO-d 6: 2.50 [D] and 39.7 [C] ppm) were used as internal references. The assignment of chemical shifts is based on standard NMR experiments (1H and 13C). TLC analyses on silica F254 and detection by UV light at 254 nm were performed. High resolution mass spectra (HRMS) were obtained (in positive or negative mode) using the electrospray ion trap (ESI) technique by collision-induced dissociation on a Bruker APEX-4 (7-Tesla) instrument. Column chromatography was performed on silica Gel 60 (230 mesh). Chemicals and reagents were purchased from Sigma-Aldrich Chemical Co. (1-Boc-ethylenediamine, 1-Boc-piperazine, 2-chlorobenzimidazole, and 4M HCl in dioxane) and Acros Organics, USA (2-chlorobenzimidazole, isothiocyanates, and isocyanates) and used without further purification. 2-(1-Piperazino)-benzimidazole.2HCl (1) and N1-(benzimidazol-2-yl)ethane-1,2-diamine.2HCl (6) were prepared according to reported literature procedures [35,36,37,38].

2.2 Synthesis

2.2.1 General synthesis of benzimidazole-thiourea derivatives (4a–j, 7b) and benzimidazole-urea derivatives (5b–e, 8b)

To a stirred solution of compounds 1 or 6 (1.1 mmol) in dry acetonitrile (10 mL), was added excess triethylamine (4 mmol) and the corresponding isothiocyanatobenzene 2a–j or isocyanatobenzene 3b–e (1.0 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under vacuum, dissolved in ethyl acetate (20 mL) and then washed with water. The organic layer was dried over anhydrous sodium sulfate and the solution was concentrated. The crude product was filtered, dried, and recrystallized from ethyl acetate/hexane.

2.2.2 4-(1H-Benzo[d]imidazol-2-yl)-N-phenylpiperazine-1-carbothioamide (4a)

Off white solid (0.53 g, 86%); mp 229–231°C; R f = 0.74 (9:1 dichloromethane/methanol), IR (KBr, cm−1) 3,399 (NH), 1,530 (C═S); 1H NMR (400 MHz, DMSO-d 6) δ 9.49 (s, 1H), 7.32–7.28 (m, 4H), 7.27–7.14 (m, 2H), 7.15–7.10 (m, 1H), 7.07–7.15 (m, 2H), 4.11–4.09 (m, 4H), 3.68–3.66 (m, 4H). 13C NMR (100 MHz, DMSO-d 6) δ 182.0 (C═S), 155.7, 141.4, 137.5, 128.5, 125.8, 124.9, 120.5, 113, 47.7, 46.02. HRMS (ESI): m/z calcd for C18H20N5S [M + H] 338.14394, found 338.14339.

2.2.3 4-(1H-Benzo[d]imidazol-2-yl)-N-(p-tolyl)piperazine-1-carbothioamide (4b)

Off white solid (0.28 g, 72%); mp 231–233°C; R f = 0.72 (9:1 dichloromethane/methanol), IR (KBr, cm−1) 3,430 (NH), 1,523 (C═S); 1H NMR (400 MHz, DMSO-d 6) δ 11.53 (s, 1H), 9.37 (s, 1H), 7.33 (m, 2H), 7.27–7.14 (m, 2H), 7.13–7.06 (m, 2H), 6.95 (m, 2H), 4.16–3.95 (m, 4H), 3.67–3.47 (m, 4H), 2.28 (s, 3H). 13C NMR (100 MHz, DMSO-d 6) δ 182.1 (C═S), 156.0, 138.7, 134.1, 130.8, 129.0, 126.2, 126.0, 120.3, 47.6, 46.0, 21.0. HRMS (ESI): m/z calcd for C19H22N5S [M + H] 352.15959, found 352.15904.

2.2.4 4-(1H-Benzo[d]imidazol-2-yl)-N-(4-methoxyphenyl)piperazine-1-carbothioamide (4c)

White solid (0.38 g, 57%); mp 285–287°C; R f = 0.77 (9:1 dichloromethane/methanol), IR (KBr, cm−1) 3,413 (NH), 1,527 (C═S); 1H NMR (400 MHz, DMSO-d 6) δ 11.46 (s, 1H), 9.31 (s, 1H), 7.16 (m, 4H), 6.86 (m, 4H), 4.13–3.94 (m, 4H), 3.73 (s, 3H), 3.64–3.52 (m, 4H). 13C NMR (100 MHz, DMSO-d 6) δ 182.2 (C═S), 156.9, 156.0, 134.2, 127.9, 126.3, 120.2, 116.5, 113.6, 55.6, 47.6, 46.10. HRMS (ESI): m/z calcd for C19H22N5OS [M + H] 368.15451, found 368.15491.

2.2.5 4-(1H-Benzo[d]imidazol-2-yl)-N-(3-chlorophenyl)piperazine-1-carbothioamide (4d)

Off white solid (0.20 g, 74%); mp 248–250°C; R f = 0.74 (9:1 dichloromethane/methanol), IR (KBr, cm−1) 3,428 (NH), 1,529 (C═S); 1H NMR (400 MHz, DMSO-d 6) δ 11.56 (s, 1H), 9.54 (s, 1H), 7.46 (m, 1H), 7.37–7.27 (m, 2H), 7.25–7.20 (m, 2H), 7.17 (m, 1H), 6.95 (m, 2H), 4.11–4.02 (m, 4H), 3.69–3.54 (m, 4H). 13C NMR (100 MHz, DMSO-d 6) δ 181.7 (C═S), 155.9, 142.9, 139.0, 132.6, 130.0, 125.1, 124.4, 123.9, 120.3, 113.0, 47.8, 46.9. HRMS (ESI): m/z calcd for C18H19ClN5S [M + H] 372.10497, found 372.10442.

2.2.6 4-(1H-Benzo[d]imidazol-2-yl)-N-(4-chlorophenyl)piperazine-1-carbothioamide (4e)

Off white solid (0.53 g, 79%); mp 246–248°C; R f = 0.71 (9:1 dichloromethane/methanol), IR (KBr, cm−1) 3,399 (NH), 1,524 (C═S); 1H NMR (400 MHz, DMSO-d 6) δ 11.48 (s, 1H), 9.50 (s, 1H), 7.63–7.40 (m, 1H), 7.34 (m, 3H), 7.22 (m, 2H), 6.94 (m, 2H), 4.17–3.98 (m, 4H), 3.70–3.51 (m, 4H). 13C NMR (100 MHz, DMSO-d 6) δ 181.8 (C═S), 156.1, 140.4, 128.8, 128.3, 127.4, 125.5, 119.6, 115.6, 47.8, 46.0. HRMS (ESI): m/z calcd for C18H19ClN5S [M + H] 372.10497, found 372.10465.

2.2.7 4-(1H-Benzo[d]imidazol-2-yl)-N-(4-nitrophenyl)piperazine-1-carbothioamide (4f)

Yellow solid (0.25 g, 91%); mp 204–206°C; R f = 0.84 (9:1 dichloromethane/methanol), IR (KBr, cm−1) 3,435 (NH), 1,530 (C═S); 1H NMR (400 MHz, DMSO-d 6) δ 11.63 (s, 1H), 9.96 (s, 1H), 8.18 (d, J = 9.2 Hz, 2H), 7.63 (d, J = 9.1 Hz, 2H), 7.23 (m, 2H), 6.96 (m, 2H), 4.13–4.06 (m, 4H), 3.68–3.60 (m, 4H). 13C NMR (100 MHz, DMSO-d 6) δ 181.3 (C═S), 155.7, 148.2, 142.6, 128.8, 124.4, 123.2, 120.4, 113.4, 48.3, 46.0. HRMS (ESI): m/z calcd for C18H19N6O2S [M + H] 383.12902, found 383.12877.

2.2.8 4-(1H-Benzo[d]imidazol-2-yl)-N-(2-fluorophenyl)piperazine-1-carbothioamide (4g)

Yellowish solid (0.21 g, 80%); mp 268–270°C; R f = 0.8 (9:1 dichloromethane/methanol), IR (KBr, cm−1) 3,458 (NH), 1,528 (C═S); 1H NMR (400 MHz, DMSO-d 6) δ 11.82 (s, 1H), 9.30 (s, 1H), 7.32–7.21 (m, 5H), 7.21–7.13 (m, 1H), 7.04–6.94 (m, 2H), 4.17–3.96 (m, 4H), 3.74–3.58 (m, 4H). 13C NMR (100 MHz, DMSO-d 6) δ 182.7 (C═S), 158.1 (d, 1 J C–F = 246.0 Hz), 151.9, 136.9, 130.6 (d, 3 J C–F = 3.5 Hz), 129.2 (d, 2 J C–F = 11.9 Hz), 128.2 (d, 3 J C–F = 7.2 Hz), 124.5 (d, 4 J C–F = 3.9 Hz), 121.1, 116.2 (d, 2 J C–F = 20 Hz), 112.5, 47.5, 46.0. HRMS (ESI): m/z calcd for C18H19FN5S [M + H] 356.13452, found 356.13397.

2.2.9 4-(1H-Benzo[d]imidazol-2-yl)-N-(3-fluorophenyl)piperazine-1-carbothioamide (4h)

White solid (0.52 g, 80%); mp 229–231°C; R f = 0.71 (9:1 dichloromethane/methanol), IR (KBr, cm−1) 3,410 (NH), 1,535 (C═S); 1H NMR (400 MHz, DMSO-d 6) δ 11.58 (s, 1H), 9.55 (s, 1H), 7.33 (td, J = 8.2, 6.8 Hz, 1H), 7.26 (dt, J = 11.2, 2.3 Hz, 1H), 7.24–7.19 (m, 2H), 7.16 (m, 1H), 7.00–6.89 (m, 3H), 4.10–4.04 (m, 4H), 3.66–3.58 (m, 4H). 13C NMR (100 MHz, DMSO-d 6) δ 181.7 (C═S), 161.5 (d, 1 J C–F = 241 Hz), 155.6, 143.3 (d, 3 J C–F = 4.5 Hz), 138.2, 129.9 (d, 4 J C–F = 3.1 Hz), 121.1, 121.0 (d, 3 J C–F = 2.9 Hz), 120.5, 112.2 (d, 2 J C–F = 24 Hz), 110.1 (d, 2 J C–F = 21 Hz), 47.9, 46.1. HRMS (ESI): m/z calcd for C18H19FN5S [M + H] 356.13452, found 356.13407.

2.2.10 4-(1H-Benzo[d]imidazol-2-yl)-N-(4-fluorophenyl)piperazine-1-carbothioamide (4i)

Beige solid (0.64 g, 98%); mp 248–250°C; R f = 0.78 (9:1 dichloromethane/methanol), IR (KBr, cm−1) 3,193 (NH), 1,569 (C═S); 1H NMR (400 MHz, DMSO-d 6) δ 11.48 (s, 1H), 9.44 (s, 1H), 7.31 (m, 2H), 7.22 (m, 2H), 7.14 (m, 2H), 6.94 (m, 2H), 4.28–3.89 (m, 4H), 3.79–3.50 (m, 4H). 13C NMR (100 MHz, DMSO-d 6) δ 182.2 (C═S), 159.7 (d, 1 J C–F = 240 Hz), 155.3, 138.1, 137.7 (d, 4 J C–F = 3 Hz), 128.2 (d, 3 J C–F = 8.3 Hz), 123.9, 120.6, 115.1 (d, 2 J C–F = 22 Hz), 47.5, 46.0. HRMS (ESI): m/z calcd for C18H19FN5S [M + H] 356.13452, found 356.13421.

2.2.11 4-(1H-Benzo[d]imidazol-2-yl)-N-(4-(trifluoromethyl)phenyl)piperazine-1-carbothioamide (4j)

White solid (0.248 g, 84%); mp 242–246°C; R f = 0.78 (9:1 dichloromethane/methanol), IR (KBr, cm−1) 3,423 (NH), 1,529 (C═S); 1H NMR (400 MHz, DMSO-d 6) δ 9.73 (s, 1H), 8.95 (s, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.27 (dd, J = 5.8, 3.2 Hz, 1H), 7.02 (dd, J = 5.7, 3.2 Hz, 1H), 4.20–4.00 (m, 4H), 3.76–3.58 (m, 4H). 13C NMR (100 MHz, DMSO-d 6) δ 181.8 (C═S), 156.0, 145.3, 129.0, 126.3, 125.6, 124.8, 124.1, 123.8, 123.6, 120.3, 48.0, 46.0. HRMS (ESI): m/z calcd for C19H18F3N5S [M + H] 406.13133, found 406.13162.

2.2.12 4-(1H-Benzo[d]imidazol-2-yl)-N-(p-tolyl)piperazine-1-carboxamide (5b)

Beige solid (0.34 g, 55%); mp 298–300°C; R f = 0.74 (9:1 dichloromethane/methanol), IR (KBr, cm−1) 3,407 (NH), 1,637 (C═O); 1H NMR (400 MHz, DMSO-d 6) δ 11.46 (s, 1H), 8.55 (s, 1H), 7.34 (m, 2H), 7.21 (s, 2H), 7.06 (m, 2H), 7.00–6.85 (m, 2H), 3.59 (dd, J = 7.1, 3.4 Hz, 4H), 3.53 (dd, J = 7.1, 3.6 Hz, 4H), 2.23 (s, 3H). 13C NMR (100 MHz, DMSO-d 6) δ 156.4 (C═O), 155.5, 138.2, 137.7, 131.1, 129.6, 129.2, 120.3, 118.6, 115.5, 109.5, 46.4, 43.6, 20.8. HRMS (ESI): m/z calcd for C19H22N5O [M + H] 336.18244, found 336.18256.

2.2.13 4-(1H-Benzo[d]imidazol-2-yl)-N-(4-methoxyphenyl)piperazine-1-carboxamide (5c)

Off white solid (0.16 g, 63%); mp 297–299°C; R f = 0.75 (9:1 dichloromethane/methanol), IR (KBr, cm−1) 3,467 (NH), 1,634 (C═O); 1H NMR (400 MHz, DMSO-d 6) δ 11.55 (s, 1H), 8.48 (s, 1H), 7.39–7.31 (m, 2H), 7.21 (m, 2H), 6.94 (m, 2H), 6.88–6.80 (m, 2H), 3.70 (s, 3H), 3.61–3.55 (m, 4H), 3.55–3.49 (m, 4H). 13C NMR (100 MHz, DMSO-d 6) δ 156.3 (C═O), 155.7, 154.9, 133.7, 133.3, 122.0, 120.3, 114.4, 114.0, 55.5, 46.4, 43.5. HRMS (ESI): m/z calcd for C19H22N5O2 [M + H] 352.17735, found 352.17744.

2.2.14 4-(1H-Benzo[d]imidazol-2-yl)-N-(3-chlorophenyl)piperazine-1-carboxamide (5d)

White solid (0.41 g, 63%); mp 287–289°C; R f = 0.68 (9:1 dichloromethane/methanol), IR (KBr, cm−1) 3,434 (NH), 1,636 (C═O); 1H NMR (400 MHz, DMSO-d 6) δ 11.46 (s, 1H, NH), 8.82 (s, 1H, NH), 7.67 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.27 (t, J = 8.4 Hz, 1H), 7.21 (m, 2H), 6.99 (d, J = 8.4 Hz, 1H), 6.94 (m, 2H), 3.63–3.57 (m, 4H), 3.56–3.50 (m, 4H). 13C NMR (100 MHz, DMSO-d 6) δ 156.4 (C5O), 155.5, 142.5, 136.2, 135.6, 131.1, 129.9, 129.6, 129.2, 120.3.1, 118.6, 46.3, 43.6. HRMS (ESI): m/z calcd for C18H19ClN5O [M + H] 356.12781, found 356.12726.

2.2.15 4-(1H-Benzo[d]imidazol-2-yl)-N-(4-chlorophenyl)piperazine-1-carboxamide (5e)

Off white solid (m = 0.304 g, 50%); mp 287–289°C; R f = 0.70 (9:1 dichloromethane/methanol), IR (KBr, cm−1) 3,259 (NH), 1,642 (C═O); 1H NMR (400 MHz, DMSO-d 6) δ 11.46 (s, 1H), 8.77 (s, 1H), 7.39 (d, J = 8.9 Hz, 2H), 7.29 (d, J = 8.9 Hz, 1H), 7.21 (m, 2H), 7.08–6.75 (m, 2H), 3.59 (dd, J = 7.1, 3.6 Hz, 4H), 3.53 (dd, J = 6.8, 3.7 Hz, 4H). 13C NMR (100 MHz, DMSO-d 6) δ 155.3, 139.2, 138.1, 137.6, 129.1, 128.3, 126.1, 120.4, 111.7, 46.4, 43.4. HRMS (ESI): m/z calcd for C18H19ClN5O [M + H] 356.12781, found 356.12726.

2.2.16 1-(2-(1H-Benzo[d]imidazol-2-ylamino)ethyl)-3-p-tolylthiourea (7b)

Beige solid (m = 0.182 g, 97%); mp 165–167°C, IR (KBr, cm−1) 3,271 (NH), 1,684 (C═S); 1H NMR (400 MHz, Methanol-d 4) δ 9.32 (s, 1H), 7.45 (s, 2H), 7.33–7.31 (m, 2H), 7.24–7.17 (m, 2H), 7.12–7.10 (m, 2H), 7.04–7.02 (m, 2H), 3.94–3.87 (m, 2H), 3.64–3.61 (m, 2H), 2.27 (s, 3H). 13C NMR (100 MHz, DMSO-d 6) δ 181.7 (C═S), 151.7, 136.1, 135.0, 131.9, 130.1, 124.5, 122.7, 122.3, 42.9, 42.4. HRMS (ESI): m/z calcd for C17H20N5S [M + H] 326.14394, found 326.14339.

2.2.17 1-(2-(1H-Benzo[d]imidazol-2-ylamino)ethyl)-3-p-tolylurea (8b)

Beige solid (m = 0.069 g, 77%); mp 100–102°C; IR (KBr, cm−1) 3,370 (NH), 1,705 (C═O); 1H NMR (400 MHz, CD3OD) δ 8.33 (s, 1H), 7.38–7.31 (m, 2H), 7.26–7.19 (m, 2H), 7.18–7.11 (m, 2H), 7.10– 7.01 (m, 2H), 6.42 (s, 1H), 3.57–3.54 (m, 2H), 3.50–3.47 (m, 2H), 2.24 (s, 3H). 13C NMR (100 MHz, DMSO-d 6) δ 157.5 (C═O), 151.2, 136.5, 132.1, 130.7, 128.9, 123.0, 119.5, 111.0, 43.4, 38.5. HRMS (ESI): m/z calcd for C17H20N5O [M + H] 310.16679, found 310.16639

2.3 Cytotoxicity assay

The cytotoxic activity of the synthesized compounds was assessed in human BC cell lines. MDA-MB-231ER(−)/PR(−) and MCF-7ER(+)/PR(+) cancer cells were obtained from German Collection of Cell Cultures (DSMZ, Germany). Cells were cultured in high glucose DMEM (UFC Biotech, Saudi Arabia) containing 1% of antibiotic (Penicillin–Streptomycin, UFC Biotech, Saudi Arabia) supplemented with 10% of fetal bovine serum (GIBCO, USA). These cells were maintained at 37°C and in 5% of CO2. Cells were seeded in 96-well plates (5 × 104 cells/well) and treated with different concentrations for 24 h. Afterwards, the medium containing the compounds was removed. Subsequently, MTT solution (5 mg mL−1) was added to each well and incubated for 2 h. Then, absorbance was read in a microplate reader (Microplate Reader, Biotek) using 550 nm wavelengths. The control received only DMSO of 0.1%. IC50 values were determined using the OriginPro 8.5 software.

2.4 Light microscopy

To investigate the effects of active compounds on the morphology of MCF-7, the cells were seeded in DMEM. The cells were treated with 2 × IC50 value for 24 h, and imaged using a light microscope (Leica, Germany) at 200× magnification.

2.5 4′,6-Diamidino-2-phenylindole (DAPI) staining assay

DAPI staining was carried according to ref. [39] with modifications. Cells were cultured in a 24-well culture plate (Nist, China) for 24 h. After incubation with 2 × IC50 of 7b and 5d for 24 h, cells were washed with PBS, fixed with ice cold methanol for 5 min and then were again washed with PBS. After washing, the cells were stained with DAPI (1 μg mL−1) and incubated in dark for 30 min. Methanol was used as a control. The cells were photographed using a fluorescence microscope (Evos, USA).

2.6 Acridine orange/ethidium bromide (AO/EB) staining

MCF-7 cells were incubated with 7b and 5d (2× IC50) as described in the Section 2.5 for 24 h, then stained with AO/EB (2 μg mL−1) for 10 min, and were viewed using fluorescence microscopy.

2.7 Caspases-3/7

The assessment of caspase-3/7 was carried out based on the manufacturer’s manual. Briefly, the cells were cultured in a 24-well culture plate (Nist, China) for 24 h. The cells were treated as described in the Section 2.5. After treatment, 1 μg mL−1 of caspase-3/7 reagent (Invitrogen, USA) was added and shaken for 30 s and incubated in dark for 30 min. Methanol was used as a control. The cells were photographed using a fluorescence microscope.

3 Results and discussion

The synthesis of thiourea and urea derivatives of benzimidazole is outlined in Scheme 1. The synthesis of target thiourea 4a–j and urea 5b–e was achieved by reacting 2-(piperazin-1-yl)-1H-benzo[d]imidazole hydrochloride 1 [30,31] with substituted isothiocyanates 2a–j and isocyanates 3b–e, respectively, in the presence of an excess of triethylamine to obtain good yields.

Scheme 1 Synthesis of benzimidazole thiourea (4a–j, 7b) and benzimidazole urea (5b–e, 8b) derivatives.
Scheme 1

Synthesis of benzimidazole thiourea (4a–j, 7b) and benzimidazole urea (5b–e, 8b) derivatives.

Similarly, two derivatives thiourea 7b and urea 8b were prepared by reacting N1-(1H-benzo[d]imidazol-2-yl)ethane-1,2-diamine hydrochloride 6 [38] with isothiocyanates 2b and isocyanates 3b, respectively. The purity of the prepared compound is confirmed by recrystallization, its melting point, chromatographic technique, and spectroscopy data.

The newly synthesized compounds (4a–j, 7b) and (5b–e, 8b) were characterized by MS, 1H and 13C NMR, and IR spectral data. These data, detailed in the experimental part, are consistent with the suggested structures. The 13C NMR data revealed the presence of a signal between 181.1 and 182.7 ppm for compounds (4a–j, 7b) and between 155.3 and 157.5 ppm for compounds (5b–e, 8b). This signal corresponds to quaternary carbons C═S and C═O, respectively. In the IR spectra, absorption bands associated with C═S and C═O stretching vibrations are appearing between 1,523 and 1,596 cm−1 for compounds (4a–j, 7b) and between 1,634 and 1,642 cm−1 for compounds (5b–e, 8b), respectively. The HRMS of the synthesized compounds are in good agreement with the calculated values.

The diversity of the proposed compounds in Scheme 1 is evident from the different functional groups (urea and thiourea), substitution on the phenyl ring including activating and deactivating groups, and also from using the piperazine and ethylenediamine as spacers. These structure variations can help investigating the structure–activity relationship.

The newly synthesized thiourea 4a–j and urea 5b–e were investigated for cytotoxicity using MTT cell viability assay in two human BC cell lines, MCF-7 and MDA-MB-231. As shown in Figures 2 and 3, only the compounds 7b and 5d were cytotoxic to the tested cancer cell lines. For the remaining compounds, the IC50 values were not calculated because they were higher than 1,000 µg mL−1. However, the cytotoxicity of compounds 7b and 5d was higher in MCF-7 with IC50 values of 25.8 and 48.3 µM, respectively, as compared with their activity on MDA-MB-231 cells. The IC50 values for 7b and 5d compounds were 54.3 and 89.5 µM, respectively, on MDA-MB-231 cells (Table 1).

Table 1

The concentration with 50% inhibition (IC50 in µM) of derivatives 7b and 5d against breast cancer cell lines, MCF7 and MDA-MB-231

MCF-7 (IC50 in µM) MDA-MB-231 (IC50 in µM)
7b 25.8 ± 0.5 54.3 ± 0.09
5d 48.3 ± 0.8 89.5 ± 0.1

Morphological alternations in the cells were observed using phase contrast microscope after incubation with 7b and 5d for 24 h. Cells in the control group retained the morphological form, most of which were adherent to the surface, tightly packed, and distinctively monolayer. Exposure of the BC cells to 7b and 5d compounds led to rounding, shrinkage of the cells, loss of contact, and debris formation (Figures 2b and c and 3b and c).

Figure 2 (a) Cytotoxic activity of 7b on MCF-7 and MDA-MB-231 cells using MTT assay; (b) control; and (c) cells treated with 7b showing shrinkage and detachment from the surface (24 h).
Figure 2

(a) Cytotoxic activity of 7b on MCF-7 and MDA-MB-231 cells using MTT assay; (b) control; and (c) cells treated with 7b showing shrinkage and detachment from the surface (24 h).

The potential of inducing apoptosis by the 7b and 5d was assessed by DAPI staining. The results indicated that the number of apoptotic cells was higher in 7b- and 5d-treated cells than DMSO control. The changes that took place in MCF-7 cells as a result of 7b and 5d treatments are represented in Figures 4a and b and 5a and b. The treatment resulted in chromatin condensation and nuclear fragmentation which are apoptotic indicators.

Figure 3 (a) Cytotoxic activity of 5d on MCF-7 and MDA-MB-231 cells using MTT assay; (b) control; and (c) cells treated with 5d showing shrinkage and detachment from the surface (24 h).
Figure 3

(a) Cytotoxic activity of 5d on MCF-7 and MDA-MB-231 cells using MTT assay; (b) control; and (c) cells treated with 5d showing shrinkage and detachment from the surface (24 h).

Figure 4 Fluorescence image of MCF-7 cells treated with DAPI, AO/EB, or caspase-3/7 regent after 24 h of treatment with 7b. DAPI staining shows chromatin condensation and nuclear fragmentation as indicated with arrows. (a) Untreated cells and (b) treated cells. AO/EB staining: (c) untreated cells and (d) treated cells. Live cells are stained evenly green, whereas apoptotic cells are characterized by shiny green and yellow-orange staining due to loss of membrane integrity and chromatin condensation. Caspase-3/7 activation: (e) untreated cells and (f) treated cells. Caspase-3/7 activation was demonstrated by green fluorescence. Magnification ×200.
Figure 4

Fluorescence image of MCF-7 cells treated with DAPI, AO/EB, or caspase-3/7 regent after 24 h of treatment with 7b. DAPI staining shows chromatin condensation and nuclear fragmentation as indicated with arrows. (a) Untreated cells and (b) treated cells. AO/EB staining: (c) untreated cells and (d) treated cells. Live cells are stained evenly green, whereas apoptotic cells are characterized by shiny green and yellow-orange staining due to loss of membrane integrity and chromatin condensation. Caspase-3/7 activation: (e) untreated cells and (f) treated cells. Caspase-3/7 activation was demonstrated by green fluorescence. Magnification ×200.

Figure 5 Fluorescence image of MCF-7 cells treated with DAPI, AO/EB, or caspase-3/7 regent after 24 h of treatment with 5d. DAPI staining shows chromatin condensation and nuclear fragmentation as indicated with arrows: (a) untreated cells and (b) treated cells. AO/EB staining: (c) untreated cells and (d) treated cells. Live cells are stained evenly green, whereas apoptotic cells are characterized by shiny green and yellow-orange staining due to loss of membrane integrity and chromatin condensation. Caspase-3/7 activation: (e) untreated cells and (f) treated cells. Caspase-3/7 activation was demonstrated by green fluorescence. Magnification ×200.
Figure 5

Fluorescence image of MCF-7 cells treated with DAPI, AO/EB, or caspase-3/7 regent after 24 h of treatment with 5d. DAPI staining shows chromatin condensation and nuclear fragmentation as indicated with arrows: (a) untreated cells and (b) treated cells. AO/EB staining: (c) untreated cells and (d) treated cells. Live cells are stained evenly green, whereas apoptotic cells are characterized by shiny green and yellow-orange staining due to loss of membrane integrity and chromatin condensation. Caspase-3/7 activation: (e) untreated cells and (f) treated cells. Caspase-3/7 activation was demonstrated by green fluorescence. Magnification ×200.

The apoptotic morphology was detected by AO/EB fluorescent staining of MCF-7 cells incubated with 7b and 5d compounds. As evident in Figures 4c and d and 5c and d, nuclei stained with green color demonstrate live cells, while greenish yellow and orange-red nuclei show apoptotic cells. The red color shows dead cells. The negative control (untreated cells) cells appeared bright green.

In apoptotic cells, caspase-3/7 activity cleaves the substrate, releasing a DNA dye, which moves to the nucleus and binds with DNA that gives shiny green fluorescence. The treated cells (Figures 4e and f and 5e and f) showed an increase in the caspase-3/7 activity after 24 h of exposure to 7b and 5d, indicating that the apoptosis induced is caspase-3/7 dependent.

Apoptosis is a highly organized physiological mechanism to destroy abnormal cells [40] and it is an attractive endpoint in anticancer agents’ research. It is induced by many effective anticancer agents [41]. A variety of compounds have been known to induce apoptosis in various human cancer cells. So it is important to screen for apoptotic inducers from synthetic anticancer compounds. There are many ways of detecting apoptosis. Detection of apoptosis using fluorescence microscope has many advantages over other methods because it does not include an enzymatic reaction that is affected by many variables such as pH, temperature, and composition buffers [42]. Single and double staining methods for detecting apoptosis (AO/EB), produce reliable and reproducible results. The results of the apoptotic cell identified by the AO/EB method are highly reproducible [43].

Induction of apoptosis is often linked to the activation of caspases. Incubation of MCF-7 cells with 7b- and 5d-induced caspase-3/7 activity is evident by a bright green fluorescence in treated cells after 24 h. Thus, apoptosis induced by 7b and 5d was caspase dependent. Both pathways, intrinsic and extrinsic pathways, activate downstream effector caspases mainly caspase-3 and caspase-7 [44]. Apoptosis is the main target in treatment strategies of cancer. Anticancer compounds that induce apoptosis are promising candidate for cancer therapy. Further studies are required to assess other pathways for apoptosis. These data provide a scientific foundation for the discovery and development of novel anticancer compounds from benzimidazole thiourea and benzimidazole urea derivatives.

4 Conclusion

In summary, we have designed and synthesized a series of 16 novel compounds (4a–j), (5b–e), 7b, and 8b that contain benzimidazole, piperazine, ethylenediamine, and urea or thiourea moieties. These compounds were characterized by using suitable spectroscopic techniques including 1H and 13C NMR, IR, and high-resolution mass spectrometry. In vitro anticancer assay against breast cancer cell lines, MCF-7 and MDA-MB-231, revealed that the cytotoxicity of compounds 7b and 5d were higher in MCF7 with IC50 values of 25.8 and 48.3 µM, respectively, as compared with their activity in MDA-MB-231 cells. These results could be a lead to prepare new benzimidazole derivatives with potent anticancer activity.

Acknowledgements

The authors are grateful to the Deanship of Scientific Research, King Saud University, for funding through Vice Deanship of Scientific Research Chairs.

  1. Funding information: The research was funded by Vice Deanship of Scientific Research Chairs, King Saud University.

  2. Author contributions: Lamia Ali Siddig carried out the synthesis experiments and characterization. Abdelouahid Samadi carried out the spectral analysis and characterization. Mohammad A Khasawneh and Haythem A. Saadeh conceived and planned the synthesis. Nael Abutaha and Mohammad A. Wadaan conceived, planned, and carried out the experiments in bioassay. Haythem A. Saadeh was in charge of overall direction and planning, and wrote the manuscript with input from all authors. All authors have read and agreed to publish the manuscript.

  3. Conflict of interest: The authors declare no conflict of interest.

  4. Ethical approval: The conducted research is not related to either human or animal use.

  5. Data availability statement: All data are included in this published article.

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Received: 2021-07-22
Revised: 2021-09-21
Accepted: 2021-09-21
Published Online: 2021-10-26

© 2021 Lamia A. Siddig et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  57. Simple modifications of nicotinic, isonicotinic, and 2,6-dichloroisonicotinic acids toward new weapons against plant diseases
  58. Synthesis, optical and structural characterisation of ZnS nanoparticles derived from Zn(ii) dithiocarbamate complexes
  59. Presence of short and cyclic peptides in Acacia and Ziziphus honeys may potentiate their medicinal values
  60. The role of vitamin D deficiency and elevated inflammatory biomarkers as risk factors for the progression of diabetic nephropathy in patients with type 2 diabetes mellitus
  61. Quantitative structure–activity relationship study on prolonged anticonvulsant activity of terpene derivatives in pentylenetetrazole test
  62. GADD45B induced the enhancing of cell viability and proliferation in radiotherapy and increased the radioresistance of HONE1 cells
  63. Cannabis sativa L. chemical compositions as potential plasmodium falciparum dihydrofolate reductase-thymidinesynthase enzyme inhibitors: An in silico study for drug development
  64. Dynamics of λ-cyhalothrin disappearance and expression of selected P450 genes in bees depending on the ambient temperature
  65. Identification of synthetic cannabinoid methyl 2-{[1-(cyclohexylmethyl)-1H-indol-3-yl] formamido}-3-methylbutanoate using modern mass spectrometry and nuclear magnetic resonance techniques
  66. Study on the speciation of arsenic in the genuine medicinal material honeysuckle
  67. Two Cu(ii)-based coordination polymers: Crystal structures and treatment activity on periodontitis
  68. Conversion of furfuryl alcohol to ethyl levulinate in the presence of mesoporous aluminosilicate catalyst
  69. Review Articles
  70. Hsien Wu and his major contributions to the chemical era of immunology
  71. Overview of the major classes of new psychoactive substances, psychoactive effects, analytical determination and conformational analysis of selected illegal drugs
  72. An overview of persistent organic pollutants along the coastal environment of Kuwait
  73. Mechanism underlying sevoflurane-induced protection in cerebral ischemia–reperfusion injury
  74. COVID-19 and SARS-CoV-2: Everything we know so far – A comprehensive review
  75. Challenge of diabetes mellitus and researchers’ contributions to its control
  76. Advances in the design and application of transition metal oxide-based supercapacitors
  77. Color and composition of beauty products formulated with lemongrass essential oil: Cosmetics formulation with lemongrass essential oil
  78. The structural chemistry of zinc(ii) and nickel(ii) dithiocarbamate complexes
  79. Bioprospecting for antituberculosis natural products – A review
  80. Recent progress in direct urea fuel cell
  81. Rapid Communications
  82. A comparative morphological study of titanium dioxide surface layer dental implants
  83. Changes in the antioxidative properties of honeys during their fermentation
  84. Erratum
  85. Erratum to “Corrosion study of copper in aqueous sulfuric acid solution in the presence of (2E,5E)-2,5-dibenzylidenecyclopentanone and (2E,5E)-bis[(4-dimethylamino)benzylidene]cyclopentanone: Experimental and theoretical study”
  86. Erratum to “Modified TDAE petroleum plasticiser”
  87. Corrigendum
  88. Corrigendum to “A nitric oxide-releasing prodrug promotes apoptosis in human renal carcinoma cells: Involvement of reactive oxygen species”
  89. Special Issue on 3rd IC3PE 2020
  90. Visible light-responsive photocatalyst of SnO2/rGO prepared using Pometia pinnata leaf extract
  91. Antihyperglycemic activity of Centella asiatica (L.) Urb. leaf ethanol extract SNEDDS in zebrafish (Danio rerio)
  92. Selection of oil extraction process from Chlorella species of microalgae by using multi-criteria decision analysis technique for biodiesel production
  93. Special Issue on the 14th Joint Conference of Chemistry (14JCC)
  94. Synthesis and in vitro cytotoxicity evaluation of isatin-pyrrole derivatives against HepG2 cell line
  95. CO2 gas separation using mixed matrix membranes based on polyethersulfone/MIL-100(Al)
  96. Effect of synthesis and activation methods on the character of CoMo/ultrastable Y-zeolite catalysts
  97. Special Issue on Electrochemical Amplified Sensors
  98. Enhancement of graphene oxide through β-cyclodextrin composite to sensitive analysis of an antidepressant: Sulpiride
  99. Investigation of the spectroelectrochemical behavior of quercetin isolated from Zanthoxylum bungeanum
  100. An electrochemical sensor for high sensitive determination of lysozyme based on the aptamer competition approach
  101. An improved non-enzymatic electrochemical sensor amplified with CuO nanostructures for sensitive determination of uric acid
  102. Special Issue on Applied Biochemistry and Biotechnology 2020
  103. Fast discrimination of avocado oil for different extracted methods using headspace-gas chromatography-ion mobility spectroscopy with PCA based on volatile organic compounds
  104. Effect of alkali bases on the synthesis of ZnO quantum dots
  105. Quality evaluation of Cabernet Sauvignon wines in different vintages by 1H nuclear magnetic resonance-based metabolomics
  106. Special Issue on the Joint Science Congress of Materials and Polymers (ISCMP 2019)
  107. Diatomaceous Earth: Characterization, thermal modification, and application
  108. Electrochemical determination of atenolol and propranolol using a carbon paste sensor modified with natural ilmenite
  109. Special Issue on the Conference of Energy, Fuels, Environment 2020
  110. Assessment of the mercury contamination of landfilled and recovered foundry waste – a case study
  111. Primary energy consumption in selected EU Countries compared to global trends
  112. Modified TDAE petroleum plasticiser
  113. Use of glycerol waste in lactic acid bacteria metabolism for the production of lactic acid: State of the art in Poland
  114. Topical Issue on Applications of Mathematics in Chemistry
  115. Theoretical study of energy, inertia and nullity of phenylene and anthracene
  116. Banhatti, revan and hyper-indices of silicon carbide Si2C3-III[n,m]
  117. Topical Issue on Agriculture
  118. Occurrence of mycotoxins in selected agricultural and commercial products available in eastern Poland
  119. Special Issue on Ethnobotanical, Phytochemical and Biological Investigation of Medicinal Plants
  120. Acute and repeated dose 60-day oral toxicity assessment of chemically characterized Berberis hispanica Boiss. and Reut in Wistar rats
  121. Phytochemical profile, in vitro antioxidant, and anti-protein denaturation activities of Curcuma longa L. rhizome and leaves
  122. Antiplasmodial potential of Eucalyptus obliqua leaf methanolic extract against Plasmodium vivax: An in vitro study
  123. Prunus padus L. bark as a functional promoting component in functional herbal infusions – cyclooxygenase-2 inhibitory, antioxidant, and antimicrobial effects
  124. Molecular and docking studies of tetramethoxy hydroxyflavone compound from Artemisia absinthium against carcinogens found in cigarette smoke
  125. Special Issue on the Joint Science Congress of Materials and Polymers (ISCMP 2020)
  126. Preparation of cypress (Cupressus sempervirens L.) essential oil loaded poly(lactic acid) nanofibers
  127. Influence of mica mineral on flame retardancy and mechanical properties of intumescent flame retardant polypropylene composites
  128. Production and characterization of thermoplastic elastomer foams based on the styrene–ethylene–butylene–styrene (SEBS) rubber and thermoplastic material
  129. Special Issue on Applied Chemistry in Agriculture and Food Science
  130. Impact of essential oils on the development of pathogens of the Fusarium genus and germination parameters of selected crops
  131. Yield, volume, quality, and reduction of biotic stress influenced by titanium application in oilseed rape, winter wheat, and maize cultivations
  132. Influence of potato variety on polyphenol profile composition and glycoalcaloid contents of potato juice
  133. Carryover effect of direct-fed microbial supplementation and early weaning on the growth performance and carcass characteristics of growing Najdi lambs
  134. Special Issue on Applied Biochemistry and Biotechnology (ABB 2021)
  135. The electrochemical redox mechanism and antioxidant activity of polyphenolic compounds based on inlaid multi-walled carbon nanotubes-modified graphite electrode
  136. Study of an adsorption method for trace mercury based on Bacillus subtilis
  137. Special Issue on The 1st Malaysia International Conference on Nanotechnology & Catalysis (MICNC2021)
  138. Mitigating membrane biofouling in biofuel cell system – A review
  139. Mechanical properties of polymeric biomaterials: Modified ePTFE using gamma irradiation
https://doi.org/10.1515/chem-2021-0093
Schlagwörter für diesen Artikel
benzimidazole; urea; thiourea; piperazine; anticancer activity; apoptosis
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Artikel in diesem Heft

  1. Regular Articles
  2. Qualitative and semi-quantitative assessment of anthocyanins in Tibetan hulless barley from different geographical locations by UPLC-QTOF-MS and their antioxidant capacities
  3. Effect of sodium chloride on the expression of genes involved in the salt tolerance of Bacillus sp. strain “SX4” isolated from salinized greenhouse soil
  4. GC-MS analysis of mango stem bark extracts (Mangifera indica L.), Haden variety. Possible contribution of volatile compounds to its health effects
  5. Influence of nanoscale-modified apatite-type calcium phosphates on the biofilm formation by pathogenic microorganisms
  6. Removal of paracetamol from aqueous solution by containment composites
  7. Investigating a human pesticide intoxication incident: The importance of robust analytical approaches
  8. Induction of apoptosis and cell cycle arrest by chloroform fraction of Juniperus phoenicea and chemical constituents analysis
  9. Recovery of γ-Fe2O3 from copper ore tailings by magnetization roasting and magnetic separation
  10. Effects of different extraction methods on antioxidant properties of blueberry anthocyanins
  11. Modeling the removal of methylene blue dye using a graphene oxide/TiO2/SiO2 nanocomposite under sunlight irradiation by intelligent system
  12. Antimicrobial and antioxidant activities of Cinnamomum cassia essential oil and its application in food preservation
  13. Full spectrum and genetic algorithm-selected spectrum-based chemometric methods for simultaneous determination of azilsartan medoxomil, chlorthalidone, and azilsartan: Development, validation, and application on commercial dosage form
  14. Evaluation of the performance of immunoblot and immunodot techniques used to identify autoantibodies in patients with autoimmune diseases
  15. Computational studies by molecular docking of some antiviral drugs with COVID-19 receptors are an approach to medication for COVID-19
  16. Synthesis of amides and esters containing furan rings under microwave-assisted conditions
  17. Simultaneous removal efficiency of H2S and CO2 by high-gravity rotating packed bed: Experiments and simulation
  18. Design, synthesis, and biological activities of novel thiophene, pyrimidine, pyrazole, pyridine, coumarin and isoxazole: Dydrogesterone derivatives as antitumor agents
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  21. Assessing encapsulation of curcumin in cocoliposome: In vitro study
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  28. Synthesis, properties, and activity of MoVTeNbO catalysts modified by zirconia-pillared clays in oxidative dehydrogenation of ethane
  29. Synthesis and crystal structure of N,N′-bis(4-chlorophenyl)thiourea N,N-dimethylformamide
  30. Quantitative analysis of volatile compounds of four Chinese traditional liquors by SPME-GC-MS and determination of total phenolic contents and antioxidant activities
  31. A novel separation method of the valuable components for activated clay production wastewater
  32. On ve-degree- and ev-degree-based topological properties of crystallographic structure of cuprite Cu2O
  33. Antihyperglycemic effect and phytochemical investigation of Rubia cordifolia (Indian Madder) leaves extract
  34. Microsphere molecularly imprinted solid-phase extraction for diazepam analysis using itaconic acid as a monomer in propanol
  35. A nitric oxide-releasing prodrug promotes apoptosis in human renal carcinoma cells: Involvement of reactive oxygen species
  36. Machine vision-based driving and feedback scheme for digital microfluidics system
  37. Study on the application of a steam-foam drive profile modification technology for heavy oil reservoir development
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  39. Preparation of composite soybean straw-based materials by LDHs modifying as a solid sorbent for removal of Pb(ii) from water samples
  40. Synthesis and spectral characterizations of vanadyl(ii) and chromium(iii) mixed ligand complexes containing metformin drug and glycine amino acid
  41. In vitro evaluation of lactic acid bacteria with probiotic activity isolated from local pickled leaf mustard from Wuwei in Anhui as substitutes for chemical synthetic additives
  42. Utilization and simulation of innovative new binuclear Co(ii), Ni(ii), Cu(ii), and Zn(ii) diimine Schiff base complexes in sterilization and coronavirus resistance (Covid-19)
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  53. Discoloration of methylene blue at neutral pH by heterogeneous photo-Fenton-like reactions using crystalline and amorphous iron oxides
  54. Optimized extraction of polyphenols from leaves of Rosemary (Rosmarinus officinalis L.) grown in Lam Dong province, Vietnam, and evaluation of their antioxidant capacity
  55. Synthesis of novel thiourea-/urea-benzimidazole derivatives as anticancer agents
  56. Potency and selectivity indices of Myristica fragrans Houtt. mace chloroform extract against non-clinical and clinical human pathogens
  57. Simple modifications of nicotinic, isonicotinic, and 2,6-dichloroisonicotinic acids toward new weapons against plant diseases
  58. Synthesis, optical and structural characterisation of ZnS nanoparticles derived from Zn(ii) dithiocarbamate complexes
  59. Presence of short and cyclic peptides in Acacia and Ziziphus honeys may potentiate their medicinal values
  60. The role of vitamin D deficiency and elevated inflammatory biomarkers as risk factors for the progression of diabetic nephropathy in patients with type 2 diabetes mellitus
  61. Quantitative structure–activity relationship study on prolonged anticonvulsant activity of terpene derivatives in pentylenetetrazole test
  62. GADD45B induced the enhancing of cell viability and proliferation in radiotherapy and increased the radioresistance of HONE1 cells
  63. Cannabis sativa L. chemical compositions as potential plasmodium falciparum dihydrofolate reductase-thymidinesynthase enzyme inhibitors: An in silico study for drug development
  64. Dynamics of λ-cyhalothrin disappearance and expression of selected P450 genes in bees depending on the ambient temperature
  65. Identification of synthetic cannabinoid methyl 2-{[1-(cyclohexylmethyl)-1H-indol-3-yl] formamido}-3-methylbutanoate using modern mass spectrometry and nuclear magnetic resonance techniques
  66. Study on the speciation of arsenic in the genuine medicinal material honeysuckle
  67. Two Cu(ii)-based coordination polymers: Crystal structures and treatment activity on periodontitis
  68. Conversion of furfuryl alcohol to ethyl levulinate in the presence of mesoporous aluminosilicate catalyst
  69. Review Articles
  70. Hsien Wu and his major contributions to the chemical era of immunology
  71. Overview of the major classes of new psychoactive substances, psychoactive effects, analytical determination and conformational analysis of selected illegal drugs
  72. An overview of persistent organic pollutants along the coastal environment of Kuwait
  73. Mechanism underlying sevoflurane-induced protection in cerebral ischemia–reperfusion injury
  74. COVID-19 and SARS-CoV-2: Everything we know so far – A comprehensive review
  75. Challenge of diabetes mellitus and researchers’ contributions to its control
  76. Advances in the design and application of transition metal oxide-based supercapacitors
  77. Color and composition of beauty products formulated with lemongrass essential oil: Cosmetics formulation with lemongrass essential oil
  78. The structural chemistry of zinc(ii) and nickel(ii) dithiocarbamate complexes
  79. Bioprospecting for antituberculosis natural products – A review
  80. Recent progress in direct urea fuel cell
  81. Rapid Communications
  82. A comparative morphological study of titanium dioxide surface layer dental implants
  83. Changes in the antioxidative properties of honeys during their fermentation
  84. Erratum
  85. Erratum to “Corrosion study of copper in aqueous sulfuric acid solution in the presence of (2E,5E)-2,5-dibenzylidenecyclopentanone and (2E,5E)-bis[(4-dimethylamino)benzylidene]cyclopentanone: Experimental and theoretical study”
  86. Erratum to “Modified TDAE petroleum plasticiser”
  87. Corrigendum
  88. Corrigendum to “A nitric oxide-releasing prodrug promotes apoptosis in human renal carcinoma cells: Involvement of reactive oxygen species”
  89. Special Issue on 3rd IC3PE 2020
  90. Visible light-responsive photocatalyst of SnO2/rGO prepared using Pometia pinnata leaf extract
  91. Antihyperglycemic activity of Centella asiatica (L.) Urb. leaf ethanol extract SNEDDS in zebrafish (Danio rerio)
  92. Selection of oil extraction process from Chlorella species of microalgae by using multi-criteria decision analysis technique for biodiesel production
  93. Special Issue on the 14th Joint Conference of Chemistry (14JCC)
  94. Synthesis and in vitro cytotoxicity evaluation of isatin-pyrrole derivatives against HepG2 cell line
  95. CO2 gas separation using mixed matrix membranes based on polyethersulfone/MIL-100(Al)
  96. Effect of synthesis and activation methods on the character of CoMo/ultrastable Y-zeolite catalysts
  97. Special Issue on Electrochemical Amplified Sensors
  98. Enhancement of graphene oxide through β-cyclodextrin composite to sensitive analysis of an antidepressant: Sulpiride
  99. Investigation of the spectroelectrochemical behavior of quercetin isolated from Zanthoxylum bungeanum
  100. An electrochemical sensor for high sensitive determination of lysozyme based on the aptamer competition approach
  101. An improved non-enzymatic electrochemical sensor amplified with CuO nanostructures for sensitive determination of uric acid
  102. Special Issue on Applied Biochemistry and Biotechnology 2020
  103. Fast discrimination of avocado oil for different extracted methods using headspace-gas chromatography-ion mobility spectroscopy with PCA based on volatile organic compounds
  104. Effect of alkali bases on the synthesis of ZnO quantum dots
  105. Quality evaluation of Cabernet Sauvignon wines in different vintages by 1H nuclear magnetic resonance-based metabolomics
  106. Special Issue on the Joint Science Congress of Materials and Polymers (ISCMP 2019)
  107. Diatomaceous Earth: Characterization, thermal modification, and application
  108. Electrochemical determination of atenolol and propranolol using a carbon paste sensor modified with natural ilmenite
  109. Special Issue on the Conference of Energy, Fuels, Environment 2020
  110. Assessment of the mercury contamination of landfilled and recovered foundry waste – a case study
  111. Primary energy consumption in selected EU Countries compared to global trends
  112. Modified TDAE petroleum plasticiser
  113. Use of glycerol waste in lactic acid bacteria metabolism for the production of lactic acid: State of the art in Poland
  114. Topical Issue on Applications of Mathematics in Chemistry
  115. Theoretical study of energy, inertia and nullity of phenylene and anthracene
  116. Banhatti, revan and hyper-indices of silicon carbide Si2C3-III[n,m]
  117. Topical Issue on Agriculture
  118. Occurrence of mycotoxins in selected agricultural and commercial products available in eastern Poland
  119. Special Issue on Ethnobotanical, Phytochemical and Biological Investigation of Medicinal Plants
  120. Acute and repeated dose 60-day oral toxicity assessment of chemically characterized Berberis hispanica Boiss. and Reut in Wistar rats
  121. Phytochemical profile, in vitro antioxidant, and anti-protein denaturation activities of Curcuma longa L. rhizome and leaves
  122. Antiplasmodial potential of Eucalyptus obliqua leaf methanolic extract against Plasmodium vivax: An in vitro study
  123. Prunus padus L. bark as a functional promoting component in functional herbal infusions – cyclooxygenase-2 inhibitory, antioxidant, and antimicrobial effects
  124. Molecular and docking studies of tetramethoxy hydroxyflavone compound from Artemisia absinthium against carcinogens found in cigarette smoke
  125. Special Issue on the Joint Science Congress of Materials and Polymers (ISCMP 2020)
  126. Preparation of cypress (Cupressus sempervirens L.) essential oil loaded poly(lactic acid) nanofibers
  127. Influence of mica mineral on flame retardancy and mechanical properties of intumescent flame retardant polypropylene composites
  128. Production and characterization of thermoplastic elastomer foams based on the styrene–ethylene–butylene–styrene (SEBS) rubber and thermoplastic material
  129. Special Issue on Applied Chemistry in Agriculture and Food Science
  130. Impact of essential oils on the development of pathogens of the Fusarium genus and germination parameters of selected crops
  131. Yield, volume, quality, and reduction of biotic stress influenced by titanium application in oilseed rape, winter wheat, and maize cultivations
  132. Influence of potato variety on polyphenol profile composition and glycoalcaloid contents of potato juice
  133. Carryover effect of direct-fed microbial supplementation and early weaning on the growth performance and carcass characteristics of growing Najdi lambs
  134. Special Issue on Applied Biochemistry and Biotechnology (ABB 2021)
  135. The electrochemical redox mechanism and antioxidant activity of polyphenolic compounds based on inlaid multi-walled carbon nanotubes-modified graphite electrode
  136. Study of an adsorption method for trace mercury based on Bacillus subtilis
  137. Special Issue on The 1st Malaysia International Conference on Nanotechnology & Catalysis (MICNC2021)
  138. Mitigating membrane biofouling in biofuel cell system – A review
  139. Mechanical properties of polymeric biomaterials: Modified ePTFE using gamma irradiation
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